"There are fly mutants that have overgrown tissues, although flies don't live long enough to accumulate the mutations required to develop cancer in mammals. But even insects have to control and regulate cell growth, which is really what the study of cancer is about."

The Manitoba, Canada, native will present his research on cell growth in the fruit fly Drosophila this weekend at the second annual award symposium honoring Weintraub, one of the founding members of the Basic Sciences Division.

Like-human machinery

Studying growth - and how it relates to cancer - in Drosophila makes sense for an important reason: The tiny, easy-to-study insect uses essentially the same molecular machinery for cell division as human cells.

Defining growth is not easy or obvious, said Prober, who entered the Hutch/University of Washington Molecular and Cellular Biology graduate program in 1996.

"Scientists use the term 'growth' loosely, often using it to describe an increase in the number of cells," he said. "What we're interested in is true cell growth - an increase in cell mass."

Prober's research focuses on the fly version of a gene called ras, one of the first cancer-promoting genes, called oncogenes, to be discovered in mammalian cells. The role of ras and other oncogenes on regulation of the cell division cycle has been well characterized, but less is known about how these genes affect cell growth.

"The fly version of ras was cloned about 15 years ago and is almost identical to the human version," he said. "But virtually all of the mammalian studies have been performed in tissue culture, and we wanted a system where we could look at its effects in an intact organism-in vivo."

Prober's chief interest is in how growth is regulated during fly development. As a model system, he studies a sac of embryonic cells, called the wing imaginal disc, which gives rise to the wing in the adult organism.

The wing imaginal disc is composed of about 50 cells in the fly embryo. Subsequent growth and proliferation occur during the larval stage, leading to approximately 100,000 cells that form the adult wing, Prober said.

"It's a nice in vivo model and lets us look at how growth is coordinated with patterning," he said. "It's more similar to what you see in people than it is to cells growing in a Petri plate."

Key finding

Prober's key finding, published last year in Cell, was that ras regulates the accumulation of cell mass, which Edgar said may help explain ras' known role in promoting cell division.

"The link between ras and the cell cycle hasn't been understood," Edgar said. "David's work is a clear demonstration that the effect of ras on the cell cycle is really a secondary effect of its role in cell growth."

The connection between cell size and cell division was made in the 1970s, Prober said.

"It really goes back to Lee Hartwell's work on the cell cycle in yeast," he said, referring to research done by the Hutch's president and director. "Growth drives cell cycle progression, which is easy to see microscopically in yeast. The same process, although harder to observe, happens in cells in other organisms."

Prober used a system that allowed him to raise or lower the levels of ras activity in the fly imaginal disc and observe the effects on cell growth and division. The cells are also tagged with a fluorescent marker to make microscopic identification easy.

"We can count the number of cells in the disc and measure the area they take up," he said. "We then use this information to calculate rates of cell division and rates of growth."

These measurements help distinguish effects on cell growth from cell division, an important distinction when comparing the process to cancer development.

"If all you affect is the cell division cycle, you basically just got a lot of smaller cells, like a pie cut into more pieces," he said. "A tumor couldn't form that way."

Another possible link

In addition to observing an effect of ras on cell growth in flies, Prober discovered another possible link to the process of cancer.

"When ras is overexpressed in a group of cells, we observed that those cells don't mix with neighboring cells, suggesting that ras is affecting cell adhesion," he said. "In cancer, adhesion plays a large part in the process - cancer cells ball up. And in metastasis, cells have to break off and go elsewhere in the body."

His current work is to see if ras directly regulates proteins known to play a role in cell adhesion.

Prober credits his "superb" colleagues in the Edgar lab for providing a stimulating environment for doing research and the fly for helping him attain his long-standing interest in studying human disease.

"I was always interested in doing something linked to human disease," he said. "Flies might seem like a stretch, but I think it's a very useful system for studying growth and how these oncogenes work. It's been encouraging that there have been reports on human and mouse cells showing similar findings."

In collaboration with Dr. Laura Johnston, a former postdoc in the Edgar lab, and Dr. Peter Gallant in Dr. Robert Eisenman's lab, Prober found that the fly version of the myc oncogene also regulates cell growth rates. "This suggests that regulation of cell growth may be a common feature of oncogenes," Prober said.

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